Anti-inflammatory TIPE2 inhibits angiogenic VEGF in retinal pigment epithelium
Introduction
Choroidal neovascularization (CNV) is a pathological feature which commonly occurs in several ocular diseases, including age-related macular degeneration (AMD), high myopia and idiopathic CNV. Vasculogenesis and angiogenesis underlying the neuroretina are the final features of CNV. The presence of CNV indicates poor visual prognosis. Retinal pigment epithelium (RPE) plays a vital role in the pathology of CNV (Bhutto and Lutty, 2012, Grossniklaus et al., 2002). Current treatment of CNV is targeted to the formed neovascularization and could only partially prevent vision deterioration. Recent studies have suggested the significance of inflammation and immunity in the early development of CNV (Grossniklaus et al., 2002, Penfold et al., 2001). Managing CNV before vasculogenesis and angiogenesis is more vision protective.
Tumour necrosis factor (TNF)-α-induced protein-8 like-2 (TIPE2 or TNFAIP8L2) is a recently identified gene. As a new member of the TNF-α-induced protein 8 family, TIPE2 negatively regulates innate and adaptive immunity, and plays an important role in inflammatory homeostasis (Sun et al., 2008). TIPE2 deficiency in mice leads to multiple organ inflammation, and TIPE2 down-regulation in humans is associated with systemic autoimmunity (Li et al., 2009, Sun et al., 2008). In addition, TIPE2 is a biomarker and inhibitor of tumour progression.
In the present study, we examine the expression of TIPE2 in normal and inflamed RPE cells to evaluate the relationship of TIPE2 with factors affecting inflammation and angiogenesis. We may also consider the novel anti-inflammatory TIPE2 as anti-angiogenic.
Section snippets
Pre-test
Animal experiments were performed in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals by the National Academy of Sciences published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The protocol was reviewed and approved by the Institutional Animal Care and Use Committee of Qilu Hospital, Shandong University.
An animal model of CNV was induced
Decreased expression of TIPE2 in experimental CNV in the pre-test
The mRNA expression of TIPE2 in the pigmented layer of the CNV samples 3 days after photocoagulation significantly decreased compared with that of the normal mice (one set for the control vs. 0.58 ± 0.05 for the CNV samples 3 days after induction, n = 3, p <0.01). The mRNA expression of TIPE2 was almost depleted at 7 days (0.94 ± 0.02 vs. 0.06 ± 0.05 at 3 d, n = 3, p < 0.001) (Fig. 1b). Same decreased protein expression of TIPE2 in the CNV samples was found in the Western blot analysis (one set for the
Discussion
CNV is a pathohistological feature which commonly occurs in several diseases, such as AMD, pathological myopia and idiopathic CNV; RPE layer and choroidal tissue are the primary pathological sites (Hageman et al., 2001, Nagineni et al., 2012, Young, 1987). During CNV formation, RPE, choroid microvascular endothelial cells and other inflammatory cells act in different stages (Grossniklaus and Green, 2004). Although vasculogenesis and angiogenesis of the choroid are the final characterisation of
Conclusion
TIPE2 exhibits an anti-inflammatory function in cultured human RPE cells; TIPE2 also exerts an anti-VEGF effect. Further studies need to be conducted to elucidate the precise function and mechanisms of TIPE2 in CNV development.
Limitation
The main limitation is that we did not test the effects of over expression of TIPE2 in RPE cells, which may provide more proof.
Funding
This project was sponsored in part by the Natural Science Foundation of Shandong Province (Grant No. ZR2012HM024) and Independent Innovation Foundation to Universities and Colleges by Jinan Science and Technology Bureau (Grant No. 201202036). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare that they have no competing interests.
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Research progress of TIPE2 in immune-related diseases
2023, International ImmunopharmacologyDecreased expression of TIPE2 in the eye under high-glucose conditions tested in vivo and in vitro
2021, International ImmunopharmacologyCitation Excerpt :Studies concerning the mechanism of TIPE2 have determined that TIPE2 acts on the T cell receptor (TCR) and Toll-like receptor (TLR) by negatively regulating the c-Jun N-terminal kinase (JNK), p38, NF-κB, phosphatidylinositol 3-kinase–Rac and NADPH oxidase-mediated signalling pathways [15,19–20]. Previously, TIPE2 has been determined to inhibit the production of the vascular endothelial growth factor (VEGF), along with major inflammatory factors (TNF-α and IL-1β), in inflamed retinal pigment epithelial (RPE) cells [21]. VEGF has been recognised as the major mediator in DR formation [22–23].
Novel tumor necrosis factor-α induced protein eight (TNFAIP8/TIPE) family: Functions and downstream targets involved in cancer progression
2018, Cancer LettersCitation Excerpt :Moreover, it also increased the expression of pro-apoptotic proteins Bax, caspase-9, caspase-3, and cleaved poly ADP ribose polymerase (PARP), and reduced the levels of anti-apoptotic proteins Bcl-xL, p-Akt, and p-ERK1/2 [68] (Fig. 3). Further, it was also found to have anti-angiogenic properties because downregulation of TIPE2 increased the levels of vascular endothelial growth factor (VEGF) [69]. Finally, it was also found to upregulate p27 through induction of interferon regulatory factor 4 signaling cascades [70] (Table 1).
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